Exploiting tumour addiction with a serine and glycine-free diet.
Exploiting tumour addiction with a serine and glycine-free diet.
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DOI：
10.1038/cdd.2017.83
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发表时间：
2017-08
影响因子：
12.4
通讯作者：
Frezza C
中科院分区：
文献类型：
--
作者：
Amelio I;Melino G;Frezza C
了解癌症代谢是揭示癌细胞致命弱点和为患者提供新的治疗干预措施的关键。虽然在发展1或癌症转化和进展2-4期间代谢途径的重新路由已被广泛表征，但这些事件的确切动态，它们在不同肿瘤类型中的分布和频率，以及它们与遗传背景的相关性在很大程度上仍然未知。在最近发表在《自然》杂志上的一篇文章中，Karen Vousden的团队评估了丝氨酸和甘氨酸（SG）饮食限制在由不同癌基因驱动的本地小鼠肿瘤模型中的作用，5导致了潜在的治疗干预领域。非必需氨基酸丝氨酸和甘氨酸现在被认为是某些类型癌症的必需代谢物。3，6丝氨酸可以通过不同的转运蛋白输入细胞，或者可以通过丝氨酸生物合成途径（SSP）中糖酵解葡萄糖的转移来产生。7外源或重新合成的丝氨酸转化为甘氨酸，并通过刺激一碳代谢，提供核苷酸，ATP，甲基化反应和抗氧化防御的来源，如谷胱甘肽和NAPDH。8癌细胞可以通过触发SSP、抑制有氧糖酵解和增加三羧酸循环的流量来对SG剥夺做出反应。这种代谢的重排支持对由受损的一碳代谢引发的氧化应激的适应，并允许细胞在这些不利条件下存活。值得注意的是，对丝氨酸饥饿的反应由p53调节，因此，p53−/−细胞无法对SG耗尽做出反应，显示出与不平衡的氧化还原防御相关的增殖和细胞活力的严重受损。这些研究表明，SG代谢可能是癌症治疗的潜在靶点。作为选择性靶向负责SG合成的酶的替代方案，Maddocks等人5推断SG剥夺可能是影响该途径的有力策略。在他们最近的研究中，他们分析了淋巴瘤（Eμ-Myc），肠道肿瘤（ApcMin/+）和胰腺癌（Pdx 1-cre; KRasG 12 D/+; trp 53 +/−和Pdx 1-cre; KRasG 12 D/+; Trp 53 R172 H/+）的不同转基因动物模型对无SG饮食的反应。这些实验表明，SG饥饿有效地提高了Eμ-Myc和ApcMin/+小鼠的存活率，这些小鼠在出生后不久就携带癌前病变。作者还测试了这种限制饮食对已建立的恶性肿瘤的影响。他们通过皮下注射人结直肠癌（HCT-116）或小鼠Eμ-Myc肿瘤细胞开发了异种移植/同种异体移植模型，并在肿瘤建立后将动物转移到SG耗尽的实验饮食中。SG限制在相对较短的治疗时间（Eμ-Myc细胞来源的肿瘤中6天无SG饮食）后减少了肿瘤体积，这与肿瘤核心中细胞死亡增加有关。10因此，作者测试了SG饮食限制与双胍和电子传递链复合物I抑制剂的组合的效果。结果强调了一个复杂的反应，表明双胍和SG剥夺可能协同限制肿瘤生长时，组合有效地防止氧化防御。在Eμ-Myc小鼠中，苯丙氨酸确实减少了肿瘤生长。然而，由于其高毒性，需要使用更耐受的类似物二甲双胍来完成研究。然而，令人惊讶的是，在缺乏...
Understanding cancer metabolism is key to revealing the Achilles’ heel of cancer cells and providing novel therapeutic interventions for patients. While the rerouting of metabolic pathways during development 1 or cancer transformation and progression 2–4 has been extensively characterised, the exact dynamics of these events, their distribution and frequency in different tumour types, and their correlation with genetic background remain largely unknown. In a recent article published in Nature, Karen Vousden’s team assesses the effect of serine and glycine (SG) dietary restriction in autochthonous mouse tumour models driven by different oncogenes, 5 leading to potential areas of therapeutic intervention. The non-essential amino acids serine and glycine are now considered essential metabolites for some types of cancers. 3, 6 Serine can be imported into the cell through different transporters or can be produced by diversion of glycolytic glucose in the serine biosynthetic pathway (SSP). 7 Exogenous or de novo-synthetised serine is converted to glycine, and by stimulating one-carbon metabolism, provides a source of nucleotides, ATP, methylation reactions, and antioxidant defences, such as glutathione and NAPDH. 8 Cancer cells can react to SG deprivation by triggering SSP, suppressing aerobic glycolysis, and increasing the flux to the tricarboxylic acid cycle. This rearrangement of metabolism supports adaptation to oxidative stress initiated by impaired onecarbon metabolism, and allows cells to survive under these adverse conditions. Notably, the response to serine starvation is regulated by p53 and, in consequence, p53−/− cells fail to respond to SG depletion, showing severe impairment of proliferation and cell viability associated with unbalanced redox defence. 9 Together, these lines of research indicate that SG metabolism can be a potential target for cancer therapy. As an alternative to selectively targeting the enzymes responsible for SG synthesis, Maddocks et al. 5 reasoned that SG deprivation could be a powerful strategy to affect this pathway. In their recent study, they analysed the response to an SG-free diet in different genetically modified animal models of lymphoma (Eμ-Myc), intestinal tumours (ApcMin/+), and pancreatic cancer (Pdx1-cre; KRasG12D/+; trp53+/− and Pdx1-cre; KRasG12D/+; Trp53R172H/+). These experiments indicated that SG starvation effectively prolongs survival of Eμ-Myc and ApcMin/+ mice, which carry pre-malignant lesions since shortly after birth. The authors also tested the impact of this restricted diet on established malignant tumours. They developed xenograft/allograft models by subcutaneous injection of human colorectal carcinoma (HCT-116) or mouse Eμ-Myc tumour cells and transferred the animals to an SG-depleted experimental diet after the tumours were established. SG restriction reduced tumour volume after relatively short periods of treatment (6 days of SG-free diet in Eμ-Myc cellsderived tumours) and this was associated with increased cell death in the tumour core.SG deprivation was also shown to increase mitochondrial metabolism. 10 Therefore, the authors tested the effects of SG dietary restriction in combination with biguanides and inhibitors of complex I of the electron transport chain. The results highlighted a complex response that suggested that biguanides and SG deprivation might synergise in restricting tumour growth when the combination effectively prevents oxidative defence. Phenoformin indeed reduced tumour growth in Eμ-Myc mice. However, due to its high toxicity, the use of the more tolerable analogue metformin was required to complete the study. Unexpectedly, in SG-deprived …
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神经元分化过程中的代谢重编程
影响因子：
12.4
作者：
通讯作者：
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影响因子：
29
作者：
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影响因子：
64.8
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通讯作者：
Sabatini, David M.
影响因子：
13.8
作者：
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影响因子：
10.5
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